scholarly journals Exploring the determinants of ethnic differences in insulin clearance between men of Black African and White European ethnicity

2021 ◽  
Author(s):  
Meera Ladwa ◽  
Oluwatoyosi Bello ◽  
Olah Hakim ◽  
Maria Linda Boselli ◽  
Fariba Shojaee-Moradie ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
African Ancestry ◽  
Tolerance Test ◽  
Insulin Clearance ◽  
Whole Body ◽  
Direct Role ◽  
Necrosis Factor Alpha ◽  
Black African ◽  
Plasma Adiponectin ◽  
Endogenous Insulin

Abstract Aim People of Black African ancestry, who are known to be at disproportionately high risk of type 2 diabetes (T2D), typically exhibit lower hepatic insulin clearance compared with White Europeans. However, the mechanisms underlying this metabolic characteristic are poorly understood. We explored whether low insulin clearance in Black African (BA) men could be explained by insulin resistance, subclinical inflammation or adiponectin concentrations. Methods BA and White European (WE) men, categorised as either normal glucose tolerant (NGT) or with T2D, were recruited to undergo the following: a mixed meal tolerance test with C-peptide modelling to determine endogenous insulin clearance; fasting serum adiponectin and cytokine profiles; a hyperinsulinaemic–euglycaemic clamp to measure whole-body insulin sensitivity; and magnetic resonance imaging to quantify visceral adipose tissue. Results Forty BA (20 NGT and 20 T2D) and 41 WE (23 NGT and 18 T2D) men were studied. BA men had significantly lower insulin clearance (P = 0.011) and lower plasma adiponectin (P = 0.031) compared with WE men. In multiple regression analysis, ethnicity, insulin sensitivity and plasma adiponectin were independent predictors of insulin clearance, while age, visceral adiposity and tumour necrosis factor alpha (TNF-α) did not significantly contribute to the variation. Conclusion These data suggest that adiponectin may play a direct role in the upregulation of insulin clearance beyond its insulin-sensitising properties.

Analysis of candidate genes in Polish families with obesity

2004 ◽  
Vol 42 (5) ◽  
Author(s):  
Malgorzata Malczewska-Malec ◽  
Iwona Wybranska ◽  
Iwona Leszczynska-Golabek ◽  
Lukasz Partyka ◽  
Jadwiga Hartwich ◽  
...  
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Body Mass ◽  
Tolerance Test ◽  
Whole Body ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Model Assessment ◽  
The Metabolic Syndrome

AbstractThis study analyzes the relationship between risk factors related to overweight/obesity, insulin resistance, lipid tolerance, hypertension, endothelial function and genetic polymorphisms associated with: i) appetite regulation (leptin, melanocortin-3-receptor (MCR-3), dopamine receptor 2 (D2R)); ii) adipocyte differentiation and insulin sensitivity (peroxisome proliferator-activated receptor-γThe 122 members of 40 obese Caucasian families from southern Poland participated in the study. The genotypes were analyzed by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) or by direct sequencing. Phenotypes related to obesity (body mass index (BMI), fat/lean body mass composition, waist-to-hip ratio (WHR)), fasting lipids, glucose, leptin and insulin, as well as insulin during oral glucose tolerance test (OGTT) (4 points within 2 hours) and during oral lipid tolerance test (OLTT) (5 points within 8 hours) were assessed. The insulin sensitivity indexes: homeostasis model assessment of insulin resistance, whole body insulin sensitivity index, hepatic insulin sensitivity and early secretory response to an oral glucose load (HOMA-IR, ISI-COMP, ISI-HOMA and DELTA) were calculated.The single gene mutations such as CWe conclude that the polymorphisms we investigated were weakly correlated with obesity but significantly modified the risk factors of the metabolic syndrome.

Expression of FOXC2 in adipose and muscle and its association with whole body insulin sensitivity

2004 ◽  
Vol 287 (4) ◽  
pp. E799-E803 ◽  
Author(s):  
Gina B. Di Gregorio ◽  
Rickard Westergren ◽  
Sven Enerback ◽  
Tong Lu ◽  
Philip A. Kern
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Whole Body ◽  
Forkhead Transcription Factor ◽  
Intravenous Glucose ◽  
Insulin Resistant ◽  
Diet Induced Obesity ◽  
Tnf Α

FOXC2 is a winged helix/forkhead transcription factor involved in PKA signaling. Overexpression of FOXC2 in the adipose tissue of transgenic mice protected against diet-induced obesity and insulin resistance. We examined the expression of FOXC2 in fat and muscle of nondiabetic humans with varying obesity and insulin sensitivity. There was no relation between body mass index (BMI) and FOXC2 mRNA in either adipose or muscle. There was a strong inverse relation between adipose FOXC2 mRNA and insulin sensitivity, using the frequently sampled intravenous glucose tolerance test ( r = −0.78, P < 0.001). However, there was no relationship between muscle FOXC2 and any measure of insulin sensitivity. To separate insulin resistance from obesity, we examined FOXC2 expression in pairs of subjects who were matched for BMI but who were discordant for insulin sensitivity. Compared with insulin-sensitive subjects, insulin-resistant subjects had threefold higher levels of adipose FOXC2 mRNA ( P = 0.03). In contrast, muscle FOXC2 mRNA expression was no different between insulin-resistant and insulin-sensitive subjects. There was no association of adipose or muscle FOXC2 mRNA with either circulating or adipose-secreted TNF-α, IL-6, leptin, adiponectin, or non-esterified fatty acids. Thus adipose FOXC2 is more highly expressed in insulin-resistant subjects, and this effect is independent of obesity. This association between FOXC2 and insulin resistance may be related to the role of FOXC2 in PKA signaling.

scholarly journals Loss of PDGF-B activity increases hepatic vascular permeability and enhances insulin sensitivity

2011 ◽  
Vol 301 (3) ◽  
pp. E517-E526 ◽  
Author(s):  
Summer M. Raines ◽  
Oliver C. Richards ◽  
Lindsay R. Schneider ◽  
Kathryn L. Schueler ◽  
Mary E. Rabaglia ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Basolateral Membrane ◽  
Tolerance Test ◽  
Whole Body ◽  
Glucose Disposal ◽  
Permeability Barrier ◽  
Loss Of Function ◽  
Transendothelial Transport

Hepatic vasculature is not thought to pose a permeability barrier for diffusion of macromolecules from the bloodstream to hepatocytes. In contrast, in extrahepatic tissues, the microvasculature is critically important for insulin action, because transport of insulin across the endothelial cell layer is rate limiting for insulin-stimulated glucose disposal. However, very little is known concerning the role in this process of pericytes, the mural cells lining the basolateral membrane of endothelial cells. PDGF-B is a growth factor involved in the recruitment and function of pericytes. We studied insulin action in mice expressing PDGF-B lacking the proteoglycan binding domain, producing a protein with a partial loss of function (PDGF-B ret/ ret). Insulin action was assessed through measurements of insulin signaling and insulin and glucose tolerance tests. PDGF-B deficiency enhanced hepatic vascular transendothelial transport. One outcome of this change was an increase in hepatic insulin signaling. This correlated with enhanced whole body glucose homeostasis and increased insulin clearance from the circulation during an insulin tolerance test. In obese mice, PDGF-B deficiency was associated with an 80% reduction in fasting insulin and drastically reduced insulin secretion. These mice did not have significantly higher glucose levels, reflecting a dramatic increase in insulin action. Our findings show that, despite already having a high permeability, hepatic transendothelial transport can be further enhanced. To the best of our knowledge, this is the first study to connect PDGF-B-induced changes in hepatic sinusoidal transport to changes in insulin action, demonstrating a link between PDGF-B signaling and insulin sensitivity.

An increase in plasma adiponectin multimeric complexes follows hypocaloric diet-induced weight loss in obese and overweight pre-menopausal women

2007 ◽  
Vol 112 (11) ◽  
pp. 557-565 ◽  
Author(s):  
Jan Polak ◽  
Zuzana Kovacova ◽  
Martin Jacek ◽  
Eva Klimcakova ◽  
Michaela Kovacikova ◽  
...  
Keyword(s):  
Weight Loss ◽  
Insulin Sensitivity ◽  
Hypocaloric Diet ◽  
Whole Body ◽  
Diabetic Patients ◽  
Model Assessment ◽  
Obese Women ◽  
Type 2 Diabetic Patients ◽  
Plasma Adiponectin ◽  
Insulin Resistant

Adiponectin is involved in the regulation of glucose and fatty acid metabolism, influences whole-body insulin sensitivity and protects arterial walls against the development of atherosclerosis. Plasma adiponectin is decreased in obese, insulin-resistant and Type 2 diabetic patients. Adiponectin circulates in plasma as high-, medium- and low-molecular-weight (‘mass’) forms (HMW, MMW and LMW respectively). The HMW form is believed to be closely associated with insulin sensitivity. The aim of the present study was to investigate whether diet-induced changes in body weight and insulin sensitivity were associated with changes in the quantity of adiponectin multimeric complexes. A total of 20 overweight or obese women (age, 39.4±9.5 years; body mass index, 32.2±6.4 kg/m2) underwent 12 weeks of low caloric diet (600 kcal/day less than energy requirements; where 1 kcal≈4.184 kJ). Plasma samples were drawn before and after the study for biochemical analysis and Western blot detection of adiponectin multimeric complexes. The hypocaloric diet resulted in a weight reduction (89.8±16.4 kg compared with 83.1±15.6 kg; P<0.001) and an improvement in whole-body insulin sensitivity, as measured by HOMA (homoeostasis model assessment index; 1.9±0.8 compared with 1.5±0.7; P=0.013). Increases in the quantities of the HMW, MMW and LMW forms by 5.5, 8.5 and 18.1% respectively, were observed (P<0.05 for all of the forms). Total plasma adiponectin was increased by 36% with borderline significance (P=0.08). No correlations between changes in adiponectin complexes and changes in indices of insulin sensitivity were observed. In conclusion, diet-induced weight loss improved insulin sensitivity as well as increased the amount of HMW, MMW and LMW adiponectin complexes in plasma.

scholarly journals Exercise training and metformin, but not exercise training alone, decreases insulin production and increases insulin clearance in adults with prediabetes

2017 ◽  
Vol 123 (1) ◽  
pp. 243-248 ◽  
Author(s):  
Richard Viskochil ◽  
Steven K. Malin ◽  
Jennifer M. Blankenship ◽  
Barry Braun
Keyword(s):  
Insulin Sensitivity ◽  
Exercise Training ◽  
Organ System ◽  
Insulin Clearance ◽  
Whole Body ◽  
Direct Effects ◽  
Insulin Production ◽  
Pharmacological Interventions ◽  
Peripheral Insulin Sensitivity ◽  
Before And After

Adding metformin to exercise does not augment the effect of training alone to boost whole body insulin sensitivity and lower circulating insulin concentrations. Although lower insulin concentrations (lower supply) following lifestyle and/or pharmacological interventions are primarily attributed to reductions in insulin secretion that match increases in peripheral insulin sensitivity (lower demand), it is unclear whether exercise and/or metformin exert direct effects on insulin production, extraction, or clearance. Thirty-six middle-aged, obese, sedentary adults with prediabetes were randomized to placebo (P), metformin (M), exercise and placebo (E+P), or exercise and metformin (E+M) for 12 wk. Fasting plasma proinsulin (an indicator of insulin production), C-peptide, insulin, and glucose were collected before and after the intervention. Peripheral insulin sensitivity (euglycemic clamp), hepatic insulin extraction, insulin clearance, body weight, and cardiorespiratory fitness were also measured. Fasting proinsulin was unchanged following P (19.4 ± 10.1 vs. 22.6 ± 15.0 pmol/l), E+P (15.1 ± 7.4 vs. 15.5 ± 7.4 pmol/l), or M (24.8 ± 18.9 vs. 16.7 ± 20.3 pmol/l) but was significantly reduced after E+M (18.6 ± 11.9 vs. 13.9 ± 6.7 pmol/l; P = 0.04). Insulin clearance was significantly greater following M (384.6 ± 19.4 vs. 477.4 ± 49.9; P = 0.03) and E+M (400.1 ± 32.0 vs. 482.9 ± 33.9; P = 0.02) but was unchanged in P or E+P. In this study, metformin combined with exercise training reduced circulating proinsulin, and both groups taking metformin increased insulin clearance. This suggests that adding metformin to exercise may augment or attenuate training effects depending on the outcome or organ system being assessed. NEW & NOTEWORTHY Exercise is increasingly viewed as medication, creating a need to understand its interactions with other common medications. Research suggests metformin, a widely prescribed diabetes medication, may diminish the benefits of exercise when used in combination. In this study, however, metformin combined with exercise training, but not exercise alone, lowered proinsulin concentrations and increased insulin clearance in adults with prediabetes. This may directly influence personalized prescriptions of lifestyle and/or pharmacology to reduce diabetes risk.

A novel approach to assess insulin sensitivity reveals no increased insulin sensitivity in mice with a dominant-negative mutant hepatocyte nuclear factor-1α

2006 ◽  
Vol 291 (1) ◽  
pp. R131-R137 ◽  
Author(s):  
B. Ahrén ◽  
G. Pacini
Keyword(s):  
Insulin Sensitivity ◽  
Tolerance Test ◽  
Dominant Negative ◽  
Insulin Clearance ◽  
Sensitivity Index ◽  
Nuclear Factor ◽  
Intravenous Glucose ◽  
Insulin Levels ◽  
Dominant Negative Mutation ◽  
Insulin Promoter

In phenotype experiments in mice, determination of dynamic insulin sensitivity often uses the insulin tolerance test. However, the interpretation of this test is complicated by the counterregulation occurring at low glucose. To overcome this problem, we determined the dynamic insulin sensitivity after inhibition of endogenous insulin secretion by diazoxide (25 mg/kg) in association with intravenous administration of glucose plus insulin (the DSGIT technique). Estimation of insulin sensitivity index (SI) by this technique showed good correlation to SI from a regular intravenous glucose tolerance test ( r = 0.87; P < 0.001; n = 15). With DSGIT, we evaluated dynamic insulin sensitivity in mice with a rat insulin promoter (β-cell-targeted) dominant-negative mutation of hepatic nuclear factor (HNF)-1α [RIP-DN HNF-1α (Tg) mice]. When insulin was administered exogenously at the same dose in Tg and wild-type (WT) mice, plasma insulin levels were higher in WT, indicating an increased insulin clearance in Tg mice. When the diazoxide test was used, different doses of insulin were therefore administered (0.1 and 0.15 U/kg in WT and 0.2 and 0.25 U/kg in Tg) to achieve similar insulin levels in the groups. Minimal model analysis showed that SI was the same in the two groups (0.78 ± 0.21 × 10−4 min·pmol−1·l−1 in WT vs. 0.60 ± 0.11 in Tg; P = 0.45) as was the glucose elimination rate ( P = 0.27). We conclude that 1) the DSGIT technique determines the in vivo dynamic insulin action in mice, 2) insulin clearance is increased in Tg mice, and 3) chronic islet dysfunction in RIP-DN HNF-1α mice is not compensated with increased insulin sensitivity.

scholarly journals Rac1 in Muscle Is Dispensable for Improved Insulin Action After Exercise in Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (8) ◽  
pp. 3009-3015 ◽  
Author(s):  
Lykke Sylow ◽  
Lisbeth L. V. Møller ◽  
Gommaar D'Hulst ◽  
Peter Schjerling ◽  
Thomas E. Jensen ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Insulin Action ◽  
Tolerance Test ◽  
Whole Body ◽  
Wild Type ◽  
Acute Bout ◽  
Insulin Resistant ◽  
Insulin Tolerance ◽  
Rac1 Activity ◽  
Sensitizing Effect

Exercise has a potent insulin-sensitivity enhancing effect on skeletal muscle, but the intracellular mechanisms that mediate this effect are not well understood. In muscle, Ras-related C3 botulinum toxin substrate 1 (Rac1) regulates both insulin- and contraction-stimulated glucose transport and is dysregulated in insulin resistant muscle. However, whether Rac1 is involved in mediating enhanced insulin sensitivity after an acute bout of exercise is unresolved. To address this question, we investigated after exercise whole-body (insulin tolerance test) as well as muscle (insulin-stimulated 2-deoxyglucose transport in isolated soleus muscle) insulin sensitivity in inducible muscle-specific Rac1 knockout (mKO) and wild-type (WT) littermate mice. Previous exercise enhanced whole-body insulin sensitivity by 40% in WT mice and rescued the insulin intolerance in Rac1 mKO mice by improving whole-body insulin sensitivity by 230%. In agreement, previous exercise significantly improved insulin sensitivity by 20% in WT and by 40% in Rac1 mKO soleus muscles. These findings suggest that muscle Rac1 is dispensable for the insulin sensitizing effect of exercise. Moreover, insulin resistance in Rac1 mKO mice can be completely normalized by previous exercise explaining why insulin resistant patients can increase insulin action with exercise despite dysfunctional Rac1 activity in muscle.

scholarly journals Tubular Secretory Clearance Is Associated With Whole-Body Insulin Clearance

2020 ◽  
Vol 105 (11) ◽  
Author(s):  
Matthew P Huber ◽  
Leila R Zelnick ◽  
Kristina M Utzschneider ◽  
Steven E Kahn ◽  
Ian H de Boer ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Kidney Disease ◽  
Cross Sectional Study ◽  
Tubular Secretion ◽  
Fat Free Mass ◽  
Insulin Clearance ◽  
Whole Body ◽  
Estimated Gfr ◽  
Cross Sectional ◽  
Insulin Metabolism

Abstract Context The kidneys eliminate insulin via glomerular and peritubular mechanisms; consequently, the kidney contribution to insulin clearance may be underestimated by the glomerular filtration rate (GFR) alone. Objective To determine associations of tubular secretory clearance with whole-body insulin clearance and sensitivity in a dedicated study of glucose and insulin metabolism. Design, Setting, and Participants We performed an ancillary, cross-sectional study of tubular secretion in the Study of Glucose and Insulin in Renal Disease (SUGAR). Hyperinsulinemic-euglycemic clamps were performed in 57 nondiabetic persons with chronic kidney disease and 38 persons without kidney disease. Intervention We measured plasma and 24-hour urine concentrations of endogenous solutes primarily eliminated by tubular secretion. Kidney clearances of secretory solutes were calculated as the amount of blood fully cleared of that solute per minute. Main Outcome Measures Whole-body insulin clearance, insulin sensitivity. Results Mean whole-body insulin clearance was 924 ± 228 mL/min. After adjustment for age, sex, Black race, fat and fat-free mass, each 20% lower estimated GFR was associated with a 13 mL/min lower insulin clearance (95% confidence interval [CI], 2-24 mL/min lower). Each 20% lower clearance of isovalerylglycine and xanthosine were associated with a 16 mL/min lower (95% CI, 5-26 mL/min lower) and 19 mL/min lower (95% CI, 7-31 mL/min lower) insulin clearance, respectively. Neither estimated GFR nor secretory solute clearances were associated with insulin sensitivity after adjustment. Conclusions These results highlight the importance of tubular secretory pathways to insulin elimination but suggest that kidney functions in aggregate contribute only modestly to systemic insulin clearance.

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